GluR2 can Drive Neuroinflammation and Cognitive Impairments Following Peripherally Repeated Lipopolysaccharide Exposures.

Neuroinflammation is being increasingly recognized as a vital factor in the development of various neurological and neuropsychiatric diseases. Lipopolysaccharides (LPS), an outer membrane component of gram-negative bacteria, can trigger innate immune responses, resulting in neuroinflammation and subsequent cognitive deficits. The expression of glutamate receptors (GluRs) on glial cells can induce glial activation. Therefore, we hypothesized that repeated LPS exposure can increase GluR levels, promoting microglial activation and ultimately affecting synaptic plasticity and cognitive function. In this study, C57/BL6 mice were repeatedly exposed to LPS to construct a neuroinflammation animal model. The levels of GluRs, inflammatory cytokines, ionized calcium-binding adaptor molecule 1, postsynaptic density protein 95, synaptophysin 38, NMDA receptor 2 A, and NMDA receptor 2B (GluN2B) were measured in the hippocampi. Furthermore, dendritic spine density in the CA1 hippocampal region was determined. Repeated LPS exposure induced cognitive impairments and microglial activation and increased GluR1 and GluR2 levels. This was accompanied by a significant decrease in GluN2B expression and dendritic spine density in the hippocampi. However, CFM-2, an α-amino-3- hydroxy-5-methyl-4-isoxazolepropionate receptor antagonist, reversed these anomalies. Furthermore, minocycline, a microglial inhibitor, reversed these anomalies and downregulated GluR2 but not GluR1 expression. In summary, we demonstrated that GluR2 plays an essential role in microglia-induced neuroinflammation, resulting in synaptic plasticity and cognitive impairment induced by repeated exposure to LPS.

Oxytocin attenuates neuroinflammation-induced anxiety through restoration of excitation and inhibition balance in the anterior cingulate cortex in mice.

BACKGROUND: Accumulative evidence suggested that the oxytocin system plays a role in socio-emotional disorders, although its role in neuroinflammation-induced anxiety remains unclear. METHOD: In the present study, anxiety-like behavior was induced in cohorts of animals through repeated lipopolysaccharide (LPS, 0.5 mg/kg, daily, Escherichia coli O55:B5) i.p. injections for seven consecutive days. These different cohorts were subsequently used for anxiety-like behavior assessment with open field test, elevated plus maze, and novelty-suppressed feeding test or for electrophysiology (EEG) recordings of miniature excitatory postsynaptic currents (mEPSCs), miniature inhibitory postsynaptic currents (mIPSCs), or local field potential (LFP) in vivo or ex vivo settings. Samples of the anterior cingulate cortex (ACC) from some cohorts were harvested to conduct immunostaining or western blotting analysis of oxytocin, oxytocin receptor, CamkII, GABA, vGAT, vGLUT2, and c-fos. The dendritic spine density was assessed by Golgi-Cox staining. RESULTS: Repeated LPS injections induced anxiety-like behavior with concurrent decreases of oxytocin, vGLUT2, mEPSC, dendritic spine, c-fos, membrane excitability, and EEG beta and gamma oscillations, but increased oxytocin receptor and vGAT expressions in the ACC; all these changes were ameliorated by oxytocin intranasal or local brain (via cannula) administration. CONCLUSION: Taken together, our data suggested that oxytocin system may be a therapeutic target for developing treatment to tackle neuroinflammation-induced anxiety.

Acute and long-term cognitive impairment following sepsis: mechanism and prevention.

INTRODUCTION: Sepsis is a severe host response to infection, which induces both acute and long-term cognitive impairment. Despite its high incidence following sepsis, the underlying mechanisms remain elusive and effective treatments are not available clinically. AREA COVERED: This review focuses on elucidating the pathological mechanisms underlying cognitive impairment following sepsis. Specifically, the authors discuss the role of systemic inflammation response, blood-brain barrier disruption, neuroinflammation, mitochondrial dysfunction, neuronal dysfunction, and Aß accumulation and tau phosphorylation in cognitive impairment after sepsis. Additionally, they review current strategies to ameliorate cognitive impairment. EXPERT OPINION: Potential interventions to reduce cognitive impairment after sepsis include earlier diagnosis and effective infection control, hemodynamic homeostasis, and adequate brain perfusion. Furthermore, interventions to reduce inflammatory response, reactive oxygen species, blood-brain barrier disruption, mitochondrial dysfunction, neuronal injury or death could be beneficial. Implementing strategies to minimize delirium, sleep disturbance, stress factors, and immobility are also recommended. Furthermore, avoiding neurotoxins and implementing early rehabilitation may also be important for preventing cognitive impairment after sepsis.

Melanin-like polydopamine nanoparticles mediating anti-inflammatory and rescuing synaptic loss for inflammatory depression therapy.

Inflammatory depression is closely related to neuroinflammation. However, current anti-inflammatory drugs have low permeability to cross blood-brain barrier with difficulties reaching the central nervous system to provide therapeutic effectiveness. To overcome this limitation, the nano-based drug delivery technology was used to synthesize melanin-like polydopamine nanoparticles (PDA NPs) (~ 250 nm) which can cross the blood-brain barrier. Importantly, PDA NPs with abundant phenolic hydroxyl groups function as excellent free radical scavengers to attenuate cell damage caused by reactive oxygen species or acute inflammation. In vitro experiments revealed that PDA NPs exhibited excellent antioxidative properties. Next, we aimed to investigate the therapeutic effect of PDA NPs on inflammatory depression through intraperitoneal injection to the lipopolysaccharide-induced inflammatory depression model in mice. PDA NPs significantly reversed the depression-like behavior. PDA NPs was also found to reduce the peripheral and central inflammation induced by LPS, showing that alleviated splenomegaly, reduced serum inflammatory cytokines, inhibited microglial activation and restored synaptic loss. Various experiments also showed that PDA NPs had good biocompatibility both in vivo and in vitro. Our work suggested that PDA NPs may be biocompatible nano-drugs in treating inflammatory depression but their clinical application requires further study.

Dysfunction of NRG1/ErbB4 Signaling in the Hippocampus Might Mediate Long-term Memory Decline After Systemic Inflammation.

Accumulating evidence has suggested that a great proportion of sepsis survivors suffer from long-term cognitive impairments after hospital discharge, leading to decreased life quality and substantial caregiving burdens for family members. However, the underlying mechanism remains unclear. In the present study, we established a mouse model of systemic inflammation by repeated lipopolysaccharide (LPS) injections. A combination of behavioral tests, biochemical, and in vivo electrophysiology techniques were conducted to test whether abnormal NRG1/ErbB4 signaling, parvalbumin (PV) interneurons, and hippocampal neural oscillations were involved in memory decline after repeated LPS injections. Here, we showed that LPS induced long-term memory decline, which was accompanied by dysfunction of NRG1/ErbB4 signaling and PV interneurons, and decreased theta and gamma oscillations. Notably, NRG1 treatment reversed LPS-induced decreases in p-ErbB4 and PV expressions, abnormalities in theta and gamma oscillations, and long-term memory decline. Together, our study demonstrated that dysfunction of NRG1/ErbB4 signaling in the hippocampus might mediate long-term memory decline in a mouse model of systemic inflammation induced by repeated LPS injections. Thus, targeting NRG1/ErbB4 signaling in the hippocampus may be promising for the prevention and treatment of this long-term memory decline.

Integrated Proteomic and Phosphoproteomic Analysis of the Hippocampus in a Mouse Model of Early Life Inflammation.

INTRODUCTION: Inflammation in early life is a risk factor for the development of neuropsychiatric diseases later in adolescence and adulthood, yet the underlying mechanism remains elusive. In the present study, we performed an integrated proteomic and phosphoproteomic analysis of the hippocampus to identify potential molecular mechanisms of early life inflammation-induced cognitive impairment. METHODS: Both female and male mice received a single intraperitoneal injection of 100 µg/kg lipopolysaccharide (LPS) on postnatal day 10 (P10). Behavioral tests, including open field, elevated plus-maze, and Y-maze tests, were performed on P39, P40, and P41, respectively. After behavioral tests, male mice were sacrificed. The whole brain tissues and the hippocampi were harvested on P42 for proteomic, phosphoproteomic, Western blot, and Golgi staining. RESULTS: Early life LPS exposure induced cognitive impairment in male mice but not in female mice, as assessed by the Y-maze test. Therefore, following biochemical tests were conducted on male mice. By proteomic analysis, 13 proteins in LPS group exhibited differential expression. Among these, 9 proteins were upregulated and 4 proteins were downregulated. For phosphoproteomic analysis, a total of 518 phosphopeptides were identified, of which 316 phosphopeptides were upregulated and 202 phosphopeptides were downregulated in the LPS group compared with the control group. Furthermore, KEGG analysis indicated that early life LPS exposure affected the glutamatergic synapse and neuroactive ligand-receptor interaction, which were associated with synaptic function and energy metabolism. Increased level of brain protein i3 (Bri3), decreased levels of PSD-95 and mGLUR5, and dendritic spine loss after early life LPS exposure further confirmed the findings of proteomic and phosphoproteomic analysis. CONCLUSIONS: Our findings demonstrated that neuroinflammation and impaired synapse may be involved in early life inflammation-induced cognitive impairment. Future studies are required to confirm our preliminary results.

Reduced inhibition underlies early life LPS exposure induced-cognitive impairment: Prevention by environmental enrichment.

Early life immune activation has negative effects on the development of central nervous system and cognitive function, yet the underlying mechanism remains unclear. Increasing evidence has demonstrated that inflammation induces changes in microglia morphology, which lead to excessive synaptic pruning and improper function of neural circuits. Therefore, we hypothesized that early immune activation induced microglia activation, contributing to synaptic and cognitive impairments in adolescent mice. To establish the animal model of early immune activation, pups received a single intraperitoneal injection of 100 µg/kg lipopolysaccharide (LPS) on postnatal 10 (P10). Environmental enrichment (EE) was conducted four hours per day during P10-P38. Behavioral tests were performed by open field (P39), elevated plus-maze (P40) and Y maze tests (P41). The protein levels of glutamic acid decarboxylas67 (GAD67), parvalbumin (PV), vesicular gaba amino acid transporter (vGAT) and vesicular glutamate transporters (vGLUT1) were determined in the hippocampi and medial prefrontal cortex (mPFC). The protein levels of nuclear factor κB (NF-κB)/p65, NF-κB/p50, interleukin-1ß (IL-1ß), tumor necrosis factor - ɑ (TNF-ɑ) were determined in the hippocampi. The dendritic spine density was evaluated in the CA1 of the hippocampus. In our study, we showed that early life LPS exposure induced microglia activation and excessive inhibitory synapse engulfment, decreased number of perisomatic puncta on both inhibitory PV interneurons and excitatory neurons, which might contribute to excitation/inhibition imbalance, dendritic spine loss, and cognitive impairment in adolescent mice. Notably, EE rescued most of these abnormalities and improved cognitive impairment. In conclusion, our study demonstrated that reduced inhibition might contribute to early life LPS exposure induced-cognitive impairment. We also provided the possibility of the protective role of EE in rescuing these long-term adverse effects.

Contribution of DNA methyltransferases to spared nerve injury induced depression partially through epigenetically repressing Bdnf in hippocampus: Reversal by ketamine.

Long-lasting pain can induce depression, which seriously affects life quality of the patients, but little is known about the underlying mechanism. Chronic neuropathic pain can modulate DNA methylation in target genes related to neuroplasticity and mood regulation, which was induced by DNA methyltransferases (DNMTs). Methylation changes of brain-derived neurotrophic factor (Bdnf) in the hippocampus are critical for neuropathic pain and depression. Thus, we hypothesized that DNMTs are required for depression genesis, probably by repressing hippocampus Bdnf gene expression in rats with neuropathic pain, which can be rescued by ketamine. In the present study, rats were randomly subjected to spared nerve injury (SNI) or sham surgery. SNI upregulated DNMTs and downregulated Bdnf and exon I in the hippocampus and induced depression behaviors, whereas blocking the upregulation of DNMTs with RG108 alleviated SNI-induced depression by up-regulation of the expression of Bdnf and exon I. In addition, we showed that a single dose of ketamine could ameliorate SNI-induced depression-like behaviors, which was related to normalization of DNMTs and Bdnf. In conclusion, our study suggested that DNMTs-induced decreased expression of Bdnf may induce the comorbid of pain and depression, which can be prevented by ketamine.